Pulmonary delivery of polyplexes for combined PAI-1 gene silencing and CXCR4 inhibition to treat lung fibrosis

Ling Ding; Chenfei Zhu; Fei Yu; Pengkai Wu; Gang Chen; Aftab Ullah; Kaikai Wang; Minjie Sun; Jing Li; David Oupický

doi:10.1016/j.nano.2018.05.005

Pulmonary delivery of polyplexes for combined PAI-1 gene silencing and CXCR4 inhibition to treat lung fibrosis

Nanomedicine. 2018 Aug;14(6):1765-1776. doi: 10.1016/j.nano.2018.05.005. Epub 2018 May 16.

Authors

Ling Ding¹, Chenfei Zhu¹, Fei Yu², Pengkai Wu¹, Gang Chen¹, Aftab Ullah¹, Kaikai Wang¹, Minjie Sun¹, Jing Li², David Oupický³

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
² Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA.
³ State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China; Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: david.oupicky@unmc.edu.

PMID: 29777878
DOI: 10.1016/j.nano.2018.05.005

Abstract

This report describes the development of polyplexes based on CXCR4-inhibiting poly(ethylenimine) derivative (PEI-C) for pulmonary delivery of siRNA to silence plasminogen activator inhibitor-1 (siPAI-1) as a new combination treatment of pulmonary fibrosis (PF). Safety and delivery efficacy of the PEI-C/siPAI-1 polyplexes was investigated in vitro in primary lung fibroblasts isolated from mice with bleomycin-induced PF. Biodistribution analysis following intratracheal administration of fluorescently labeled polyplexes showed prolonged retention in the lungs. Treatment of mice with bleomycin-induced PF using the PEI-C/siPAI-1 polyplexes resulted in a significant down-regulation of the PAI-1 expression and decreased collagen deposition in the lung. The results of this study provide first evidence of the potential benefits of combined inhibition of CXCR4 and PAI-1 in the pulmonary treatment of PF.

Keywords: CXCR4; Intratracheal administration; PAI-1; Pulmonary fibrosis; siRNA.

Published by Elsevier Inc.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibiotics, Antineoplastic / toxicity
Apoptosis
Bleomycin / toxicity
Cell Proliferation
Cells, Cultured
Drug Delivery Systems*
Fibroblasts / metabolism
Fibroblasts / pathology
Gene Silencing
Male
Mice
Mice, Inbred C57BL
Polyethyleneimine / chemistry*
Polymers / administration & dosage*
Polymers / chemistry
Pulmonary Fibrosis / chemically induced
Pulmonary Fibrosis / genetics
Pulmonary Fibrosis / prevention & control*
RNA, Small Interfering / genetics*
Receptors, CXCR4 / antagonists & inhibitors*
Receptors, CXCR4 / genetics
Serpin E2 / antagonists & inhibitors*
Serpin E2 / genetics

Substances

Antibiotics, Antineoplastic
CXCR4 protein, mouse
Polymers
RNA, Small Interfering
Receptors, CXCR4
Serpin E2
Serpine2 protein, mouse
Bleomycin
Polyethyleneimine